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Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 8008008 Barohn et al. 1994
A 23-year-old man with no genetic diagnosis. Presented with epilepsy and a past history of abdominal pain. Electrophysiologic studies demonstrated a peripheral neuropathy with features of axonal degeneration and demyelination.

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 24353603 Chen et al., 2013
46yo Chinese woman with a biochemical diagnosis of HCP. Phenotype: acute abdominal pain and progressive bilateral weakness and pain in the limbs. She also experienced significant muscle atrophy and decreased strength. Nerve conduction potential study revealed motor-sensory polyneuropathy. Successfully treated with hemin.

PMID: 24156084 Jiménez-Jiménez et al., 2013
44-year-old patient presenting clinically with acute ataxia who was diagnosed with HCP. Heterozygous for p.Q306X.

PMID: 35228944 Upchurch et al., 2025
26-year-old female with HCP who presented with acute ascending flaccid paralysis and respiratory failure after COVID-19 infection and was initially misdiagnosed and treated for Guillain-Barré syndrome. Patient developed progressively worsening abdominal pain; symmetric, distal-predominant, and ascending weakness developed four weeks later, associated with severe headaches and complex visual hallucinosis. Electrodiagnostic testing: profound axonal sensorimotor peripheral polyneuropathy affecting all extremities. No abnormalities on brain MRI. Successfully treated with hemin. Heterozygous for c.1070G>A (p.Cys357Tyr) - rare in gnomAD v4, Revel score = 0.9. Seq method: unknown.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).
Hereditary neuropathy or pain disorder v7.8 CPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).; to: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Hereditary neuropathy or pain disorder v6.148 ARSA Sarah Leigh Tag Q3_24_promote_green was removed from gene: ARSA.
Tag Q3_24_NHS_review was removed from gene: ARSA.
Hereditary neuropathy or pain disorder v6.148 ARSA Sarah Leigh edited their review of gene: ARSA: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.147 ARSA Sarah Leigh Source Expert Review Green was added to ARSA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v5.19 ARSA Alexander Rossor commented on gene: ARSA: Now a broad panel so this gene should be includedin R78
Hereditary neuropathy or pain disorder v5.14 ARSA Sarah Leigh Tag Q3_24_promote_green tag was added to gene: ARSA.
Tag Q3_24_NHS_review tag was added to gene: ARSA.
Hereditary neuropathy or pain disorder v5.14 ARSA Sarah Leigh Publications for gene: ARSA were set to
Hereditary neuropathy or pain disorder v5.13 ARSA Sarah Leigh reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 1670590, 9600244, 1673291, 1684088; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy or pain disorder v5.13 ARSA Sarah Leigh Phenotypes for gene: ARSA were changed from Severe late infantile form with mental retardation and severe course. Regression before 30 months; adult onset, psychiatric symptoms, leukodystrophy on MRI, progressive neuropathy with SNCV, optic atrophy; Metachromatic leukodystrophy, 250100 to Metachromatic leukodystrophy, OMIM:250100; metachromatic leukodystrophy, juvenile form, MONDO:0009591
Hereditary neuropathy or pain disorder v4.11 ARSA Alexander Rossor edited their review of gene: ARSA: Added comment: Peripheral neuropathy is a well recognised feature of metachromatic leukodystrophy; Changed publications to: 31684987; Changed phenotypes to: Metachromatic leukodystrophy. Severe late infantile form with mental retardation and severe course. Regression before 30 months, adult onset, psychiatric symptoms, leukodystrophy on MRI, progressive neuropathy with SNCV, optic atrophy
Hereditary neuropathy or pain disorder v0.28 ARSA Louise Daugherty commented on gene: ARSA: Gene rated as Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Metachromatic leukodystrophy - broader phenotype
Hereditary neuropathy or pain disorder v0.28 ARSA Louise Daugherty Classified gene: ARSA as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v0.28 ARSA Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.28 ARSA Louise Daugherty Gene: arsa has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v0.1 ARSA Ellen McDonagh gene: ARSA was added
gene: ARSA was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: ARSA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ARSA were set to Severe late infantile form with mental retardation and severe course. Regression before 30 months; adult onset, psychiatric symptoms, leukodystrophy on MRI, progressive neuropathy with SNCV, optic atrophy; Metachromatic leukodystrophy, 250100